Purpose :
Rho-associated protein kinase (ROCK) has been implicated in the development of retinal neovascularization (NV) and vascular leakage in wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). We have previously shown that AR-13154(S), a selective multi-kinase inhibitor of ROCK/PKC/JAK/PDGFR-b, has therapeutic potential as a treatment option for wet AMD and PDR, either as monotherapy and in combination with anti-VEGF agents. This study assesses the pharmacokinetic (PK) and efficacy profiles of AR-13154(S) when delivered via the sustained delivery of a sub-conjunctival (SC) depot or via the pulsatile delivery of topical eye drops.

Methods :
In the oxygen-induced retinopathy (OIR) animal model, 7-day old neonatal C57BL/6 mice were housed with their mothers at 75% oxygen from postnatal day (P) 7 to P12. Upon return to normoxia on P12, mice were treated with AR-13154(S) either as a 0.06% topical eye drop, t.i.d., or via a 1-mL SC depot containing 1mg/mL of AR13154(S) in thermosensitive gel. In the PK study, animals were sacrificed on P15 and AR-13154(S) drug concentrations in the retina were measured. In the efficacy study, mouse pups were euthanized on P17, and their retinas were flat-mounted and stained for NV quantification.

Results :
In the OIR model, topical treatment with 0.06% AR-13154(S) t.i.d. resulted in a ~37% reduction of NV, whereas the SC-depot of 1mg/mL of AR13154(S) resulted in a ~64% reduction in NV, when compared to respective placebo controls. PK analysis showed that no AR-13154(S) was detected in the retinas in either treatment group. AR-13154 was shown to be converted to its active metabolite in the retina at therapeutic levels in both groups. The amount of reduction in NV in the SC-depot group showed direct correlation to concentration of the active metabolite in the retina.

Conclusions :
Sustained delivery of AR13154(S) improved the PK and efficacy profile of AR-13154(S) in the retina, which resulted in greater reduction in NV area in the OIR model relative to topical t.i.d. delivery. This study illustrates the potential of sustained delivery of ROCK inhibitors for the treatment of vascular diseases of the eye.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.